Transport by OATP1B1 and OATP1B3 enhances cytotoxicity of EGCG and certain substituted quercetins

Abstract

Organic Anion Transporting Polypeptide (OATP) 1B1 and 1B3 are multispecific uptake transporters expressed in human hepatocytes. Certain tumors also express OATP1B3. Flavonoids like quercetin and the green tea catechins have been shown to have anticancer activity in cancer cell lines. In the present study we investigated to what extent several substituted quercetins (code name: QC) would affect transport mediated by OATP1B1 and OATP1B3. We measured uptake of the radiolabeled model substrates estradiol‐17β‐glucuronide, estrone‐3‐sulfate and dehydroepiandrosterone sulfate (DHEAS) in the absence and presence of the QC compounds in stable Chinese Hamster Ovary (CHO) cells expressing OATP1B1 or OATP1B3. Most of the QC compounds were inhibitors of OATP‐mediate uptake suggesting that they could also be substrates. QC6 was a stimulator of OATP1B3‐ mediated uptake of estradiol‐17β‐glucuronide by decreasing the apparent Km value. We could demonstrate with cytotoxicity assays that EGCG and most QC compounds preferentially killed OATP‐expressing CHO cells. EGCG and QC3 were among the most cytotoxic compounds and killed OATP1B3 expressing cells selectively. Thus, EGCG and QC compounds could be promising lead compounds for the development of novel anticancer drugs to target OATP1B3‐expressing cancers such as pancreas, prostate, colon or breast cancers.